Visceral obesity markedly increases all-cause mortality by posing risks for the development of degenerative and inflammatory diseases, such as type 2 diabetes, cardiovascular disease, and some cancers. The annual U.S. obesity-attributable medical expenditures were estimated at $75 billion in 2003. These costs will continue to rise if obesity is not successfully treated.
Obesity is a complex psychosomatic disorder, which depends on a person's lifestyle and basal metabolism. Obesity results from energy consumption being greater than energy expenditure. The excess calories are converted to triglycerides, which are stored in unilocular white adipocyte in white adipose tissue. The predisposition to obesity is rooted in an efficient, thrifty metabolism, which prefers fat storage over energy expenditure.
Abdominal obesity is associated with enlarged fat depots around vital organs, known as visceral or omental fat, which produces a large amount of inflammatory cytokines. These cytokines provoke insulin resistance and chronic inflammation, two conditions influencing a variety of degenerative diseases including cancer, osteoporosis, type 2 diabetes, and cardiovascular diseases, as well as inflammatory responses in autoimmune diseases (including lupus). These pathologies lead to morbidity, disabilities, and mortality, raising the costs for medical treatment. For example, abdominal obesity increases risk of premature death from all causes, cancer and cardiovascular diseases from 50 to 100%. Successfully treating visceral obesity should help decrease the morbidity and mortality associated with these diseases. Correspondingly, a successful visceral obesity treatment will also decrease the healthcare costs associated with these diseases.
Obesity is typically treated by encouraging a change in lifestyle which can be supplemented by surgical intervention and pharmacological treatments. Although lifestyle changes can effectively lower adipose mass, patients often do not comply over the long term resulting weight regain. Moreover, change in lifestyles does not specifically reduce the visceral obesity that increases patients' risks for development of cancers and other degenerative disorders.
The harmful effects of visceral obesity may be mitigated in part by reducing white adipose tissue, including abdominal visceral fat. A majority of adipocytes in white fat tissue are lipogenic adipocytes which generate and store large amounts of lipids and have a unilocular appearance. White fat tissue also contains rare interspersed thermogenic adipocytes that have many mitochondria and produce heat utilizing stored lipids. In contrast to lipogenic adipocytes, thermogenic adipocytes burn fat to produce heat instead of storing it. Additionally, thermogenic adipocytes have a multilocular appearance due to the increased lipolysis releasing the esterified fatty acids used for heat production.
In rodents and other small mammals, thermogenic adipocytes are localized in brown fat, a specific organ maintaining body temperature. In humans, brown fat is transiently present in childhood. In adult humans, body temperature is maintained by interspersed thermogenic adipocytes, perivascular brown adipocytes, and muscle activity.
Increasing the proportion of thermogenic versus lipogenic adipocytes in white adipose tissue is associated with the reduced fat accumulation, decreased inflammation, and improved insulin sensitivity in rodents and humans. Thermogenic adipocytes have increased basal metabolic energy expenditure fueled by increased lipid consumption. Although thermogenic adipocytes offer an effective protection against obesity it is difficult to therapeutically increase the number of thermogenic adipocytes in humans.
The number of thermogenic adipocytes in white fat depends on genetic and environmental factors. Cold exposure and activation of β-adrenergic receptors stimulate conversion of lipogenic adipocytes into thermogenic adipocytes. This conversion leads to weight loss and improvement of metabolic parameters in human and animals. However, current pharmacological treatments targeting β-adrenergic receptors are associated with cardiovascular side effects and, as such, are not a suitable for obesity therapies.
Several genes and signaling pathways have been implicated either in the regulation of thermogenesis or in increasing the numbers of thermogenic adipocyte numbers in white fat. For example, thermogenesis is mediated by a family of mitochondrial uncoupling proteins (UCP1-5), which dissipate the proton gradient in mitochondria before it can be used to provide the energy for ATP synthesis. Among these proteins, UCP1 plays a pivotal role in energy uncoupling and is expressed in thermogenic adipocytes in abundance. Overexpression of UCP1 in white fat tissue reduces adiposity, improves glucose tolerance, and decreases food intake in both diet-induced and genetically obese mouse models.
Signaling pathways regulate cumulative effects resulting in an increased number of thermogenic adipocytes. For example, insulin signaling depends on the activity of mammalian target of rapamycin (mTOR kinase) complex and phosphorylation of its immediate target p70S6. Genetic deficiency in both raptor, a protein in the mTOR kinase complex, and p70S6 increases the number of thermogenic adipocytes in white fat. In animal models of obesity, changes in the activity of these genes in fat tissue were associated with the resistance to high-fat diet-induced obesity, insulin resistance, and chronic inflammation. Additionally, the thermogenic potential of adipocytes depends on activation of the transcriptional factor PPARγ, a key transcriptional regulator of adipogenesis, and its co-activator PGC1α, CCAAT/Enhancer-binding Proteins (C/EBP β) and PR domain containing 16 (PRDM16). Overexpression of these genes in lipogenic adipocytes increases biogenesis of mitochondria, UCP1 expression, and the overall thermogenic potential of adipocytes.
Vitamin A metabolism regulates these ‘high-low’ energy expenditure gene programs of adipocytes. Vitamin A metabolism proceeds in two enzymatic steps: 1) alcohol dehydrogenase family of enzymes oxidizes vitamin A to retinaldehyde; and then 2) retinaldehyde is oxidized to retinoic acid by retinaldehyde dehydrogenase family of enzymes (Aldh1 also referred to as Raldh). Retinoic acid regulates transcriptional activity of multiple nuclear receptors, whereas retinaldehyde inhibits transcriptional responses of a key transcriptional regulator of adipocyte differentiation, PPARγ. Deficiency in one Aldh1 enzyme, Aldh1A1, increases retinaldehyde levels in adipose tissue and prevents obesity and insulin resistance in Aldh1A1−/− mice on a high-fat diet. This resistance is associated with increased body temperature, UCP1 expression, and number of thermogenic cells.
While these genes and signaling pathways regulate the thermogenic potential of adipocytes, safe treatments that take advantage of these pathways are not yet available. A potential treatment to take advantage of these pathways involves genetic manipulation of adipocytes to increase their thermogenic capacity. However, gene based therapies present a long list of potential safety and regulatory concerns. Additionally, reliable gene delivery systems are not yet available and gene based treatments are extremely expensive, permanent, and run the risk of devastating side effects such as the development of cancer.
Another potential treatment involves identifying pharmaceutical compounds that increase the thermogenic capacity of adipocytes by affecting these pathways. However, developing pharmaceutical agents is also extremely expensive and can present significant safety and regulatory concerns. Moreover, systemically administered pharmaceutical agents can also have devastating side effects and may not selectively target visceral fat depots.
An additional therapeutic approach could be to manipulate the thermogenic profile of cells, such as stem cells or white adipocytes, from the subject in need of treatment for autologous transplantation back into the subject. However, this type of treatment would have to be tailored to each individual, greatly increasing the costs of treatment. Compared to stem cell therapy, transplantation of engineered cells has advantages: 1) engineered fat cells are not transformed in the body into different type of cells, 2) they generate desired effects at constant, engineered, levels. However, delivery of engineered cells for therapy in humans faces considerable obstacles. Cell implants could be rejected by the immune system. Moreover, it would be difficult to control the duration of treatment with these cells and the cells could propagate in the body.
A safe and effective treatment for obesity that increases the thermogenic capacity of adipocytes is needed. The treatment should be cost effective, safe, controllable, and available to a large population without the need for extensive tailoring to individuals. Therapies that take advantage of thermogenic genes and signaling pathways may provide a successful treatment for obesity which can, correspondingly, treat or decrease the other metabolic and inflammatory diseases associated with obesity.